Ll ruolo dell'agobiopsia nella paziente candidata alla neoadiuvante - GISMa
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ll ruolo dell’agobiopsia nella paziente
candidata alla neoadiuvante
Prof. Patrizia Querzoli
Struttura Semplice di Patologia Mammaria
U.O Anatomia Patologica
Azienda Ospedaliero-Universitaria Ferrara
patrizia.querzoli@unife.it centrodisenologiaferrara@ospfe.it
RUOLO DELL’ AGOBIOPSIA NELLA PAZIENTE CANDIDATA A NAT
Cain H et al, 2017
Cain H et al, 2017
16° St Gallen International Breast Cancer Conference-2019
Estimating the Benefits of Therapy for Early Stage Breast Cancer
The St Gallen International Consensus Guidelines for the Primary Therapy of Early Breast Cancer 2019
The Panel strongly endorsed the use of NST
as the preferred approach to stage 2 or 3 TNBC
This preference is based on the opportunity:
-to surgically downstage many patients,
-to deliver effective systemic therapy,
-to gain insights into the prognosis for a given patient
-to tailor both local and systemic therapy based
on the extent of residual disease
NST is the preferred approach for
stage 2 or 3, HER2-positive tumors and achieves
robust rates of pathological complete response
Balic M et al, 2019; Morigi C, 2019; Burstein HJ et al, 2019
Treatment should be carried out in specialised breast units/centres and provided by a multidisciplinary team specialised in breast cancer, consisting of at least medical oncologists,breast surgeons, radiation oncologists, breast radiologists, breast pathologists and breast nurses Patient information and involvement in decision making. Information on diagnosis and treatment choice should be given repeatedly (both verbally and in writing) in a comprehensive and easily understandable form NeoAdjuvant systemic treatment The decision on neoadjuvant systemic treatment should be based on the predicted sensitivity to particular treatment types, the benefit from their use and an individual’s risk of relapse Primary neoadjuvant systemic therapy. In locally advanced and large ‘operable’ cancers, in particular when mastectomy is required due to tumour size, PST is recommended to decrease the extent of surgery needed . In operable cases, the timing of treatment (pre- versus postoperative) has no effect on long-term outcomes, except a possible small increase in locoregional recurrences in the PST group, but without impact on survival. In subtypes highly sensitive to ChT, such as triple-negative and HER2-positive, a neoadjuvant approach should be preferred, in tumours >2 cm.
NAT -RUOLO DEL PATOLOGO
DIAGNOSI PRE-TERAPIA NEOADIUVANTE SU T
Accurata diagnosi del tumore e della sua biologia per selezionare le pazienti eleggibili a NAC e corretto inquadramento terapeutico
Modalità di Prelievo
-CB prelievi multipli (4-6 frustoli)
. diagnosi inequivocabile di carcinoma infiltrante, eterogeneità tumorale (CAL, DCIS)
. valutazione e confronto della cellularità tumorale pre-NAC vs cellularità residua post-NAC (richiesta da
alcuni grading)
. accurata determinazione ER,PR,KI67,HER2
.ulteriore prelievo per ricerca traslazionale
-Clip nell’area tumorale
Report Diagnostico Istopatologico su CB
. Carcinoma infiltrante, istotipo
. Grado istologico/grado nucleare
. Cellularità -% sul totale del’agobiopsia
. DCIS, istotipo, grading e %
. Presenza di microcalcificazioni
. Invasione vascolare
. Parametri predittivi (ER, PR, HER2, Ki-67)
Diagnosi pre-operatoria può essere
l’unica diagnosi se pCR
Marchiò C, et 2011
NAC –RUOLO DEL PATOLOGO DIAGNOSI PRE-TERAPIA NEOADIUVANTE SU N . Valutazione Clinico-strumentale del cavo ascellare . CB o FNA su N sospetti /clinicamente positivi. Clip su LN positivo
INVASIVE CARCINOMA -Histologic type (WHO) -Grade -Cellularity AIOM-SIAPEC -Lymphovascular invasion - ER,PR, HER2, KI67 - TILs DUCTAL CARCINOMA IN SITU -Architectural patterns GIPAM -Nuclear grade -Necrosis -Microcalcifications
ROLE OF PATHOLOGY BEFORE NEOADJUVANT TREATMENT
Processing and Reporting of Breast Specimens in the Neoadjuvant Setting
INITIAL DIAGNOSIS
-A core needle biopsy is strongly recommended.
-An unequivocal diagnosis of invasive BC , tumor type, tumor grade,
ER, PR, HER2, KI67and any other ancillary tests used to select treatment are required
before neoadjuvant treatment can be considered
-Is essential to ensure that any uncertainty about the diagnosis, need for additional
tissue for ancillary testing, or questions about the size of the primary tumor are
addressed.
For example, additional sampling may be more appropriate for a patient with
predominantly in situ carcinoma or a papillary carcinoma on core biopsy even in the
presence of a large lesion on imaging.
If the amount of invasive carcinoma on the core biopsy is very small additional
sampling to assess ER, PR, HER2, KI67 and other tests (for example multigene assays)
to help determine treatment may be helpful.
Bossuty V, 2018EVALUATION OF THE AXILLA
-Knowledge of axillary lymph node status before neoadjuvant treatment determines
prognosis and informs treatment decisions.
-Routine axillary ultrasound with core needle biopsy or fine needle aspiration of lymph
nodes, that are abnormal by clinical or ultrasound examination, is recommended.
-Positive lymph nodes are documented and response after neoadjuvant treatment can still
be assessed because the positive lymph nodes have not been removed.
CLIPS
-Clip placement in the primary tumor and in any biopsied lymph node is recommended.
-If the response to neoadjuvant treatment is good it may not be possible to identify the
correct area of the breast for surgery or for pathology sampling without placement of a clip.
-Clip placement in the axillary lymph node with localization and removal of the clipped lymph
node improves the accuracy of post-neoadjuvant treatment sentinel lymph node biopsy
Bossuty V, 201816° St Gallen International Breast Cancer Conference-2019
CONCORDANZA CB vs SS
1710 pts ( 1233 HR pos, 417 HR neg, 60 (3,5%) HR discordance pts)
Concordance rate : 96,5% ER, 91,6 %PR, 95,3 %HER2 ,
KI67 81,5% ( median CB 15% vs SS 20%)
Core needle biopsy specimens were fixed immediately in adequate volume of 4%
buffered formaldehyde and embedded in paraffin for histopathological analysis.
A minimum fixation time of 6 h was ensured, according to (ASCO/CAP) guidelines
The accuracy of CNB for breast cancer diagnosis is more than 95%.
The accuracy rates between CB and SS :
ER (61.7–99.0%,) PR 61.5–97.1%, HER2 (64.2–98.8%)
Zhu S et al, 2019ACCURATEZZA KI67 FASE PRE-ANALITICA E ANALITICA
-Multiple factors might affect Ki-67 staining and its measurement.
Type of biopsy, time to fixation,type of fixative, time in fixative, storage type, and
measurement method.
Regarding tissue type, the International Ki-67 in Breast Cancer Working Group commented
that both core biopsies and whole sections from excision are acceptable.Some studies have
suggested that whole sections may give higher Ki-67 scores than CB.
Fixation is better controlled for CB, allowing safer antigen preservation for IHC.
Fixation issues can frequently cause differences in the appearance of stained nuclei.
More rapidly fixed C B consistently showed well-circumscribed, uniformly staining nuclei,
whereas nuclei in whole sections often showed areas of highly variable staining
Unlike CB surgical specimens are inevitably exposed to varying periods of ischemia during
tumor removal. This hypoxic damage could result in apoptosis of cancer cells in surgical
samples, causing a lower proliferation index.
Another major cause of discordance is intratumoral heterogeneity of the Ki-67 index in BC.
CB contains considerably fewer tumor cells than surgical specimens and is acquired mostly
from the central portion of the tumor.There is no consensus on which region to score
(average measurement; hot spot area measurement) or the superiority of a digital image
analyzer versus manual analysis.
Dowsett M et al 2011; Polley MY et al, 2013; Romero Q et al, 2011, Ahn S et al, 2018KI67 CB vs SS FISSAZIONE, MISURAZIONE, ETEROGENEITA’ CB SS
NAT- HER2 POSITIVO-ETEROGENEITA’ INTRATUMORALE
3-4 AGOBIOPSIE
3-4 agobiopsieCARCINOMA HER2 POSITIVO- COMPLESSITA’ BIOLOGICA
Demonstration of five HER2 staining patterns of HER2-
positive breast cancer using HER2 gene-protein assay (GPA) shown
with drawings (a, d, g, j, m), HER2 GPA images (b, e, h, k, n; 9600),
and H&E images (c, f, i, l, o; 9600). In drawings and GPA images,
brown circles indicate HER2 protein while black dots and red dots
indicate HER2 gene and chromosome 17 centromere, respectively.
Classic HER2-positive pattern (Type 1) consists of homogeneous
HER2 gene and protein-positive tumor cell populations (a–c).
Another homogenous pattern (Type 2) of HER2 positive breast
cancer is amplified HER2 gene tumor cells without HER2 protein
overexpression (d–f).
One type of HER2 heterogeneity (Type 3) is amixture of two types
of breast cancer cell populations (HER2 gene and protein-positive
tumor cells and HER2 gene and protein-negative tumor cells, g–i)
Second type of HER2 heterogeneity (Type 4) is also
a mixture of two breast cancer cell populations (amplified HER2 gene
tumor cells with or without HER2 protein overexpression, j–l).
Theother type of HER2 heterogeneity (Type 5) is a mixture of Types 3
and 4 cell types (m–o)
HOU, 2017Beca F et al, 2016
-Preoperative systemic therapy, though primarily used to downstage breast cancers, can
offer, using pathologic complete response (pCR) as an endpoint, a rapid assessment of effi
cacy of a given therapeutic approach, particularly in TNBC and HER2-positive BC.
-Almost all trials have demonstrated that pCR is a robust prognostic marker in patients
with TNBC and HER2-positive cancers, so part of this discrepancy may be due to
inadequate power in the preoperative trials and/or due to the heterogeneous nature of
breast cancers.
-There is considerable interest in the use of neoadjuvant endocrine therapy (NET). The rate
of pCR to NET in HR-positive cancers is low, leading to the use of surrogate markers,
including changes in Ki-67, as biomarker of effi cacy.
-Overall, the use of neoadjuvant approaches offers a rapid assessment of efficacy of novel
therapies and remains a useful research tool for drug evaluation.
CONCLUSION
Depending on breast cancer subtype, the neoadjuvant setting allows a rapid, cost-effective
means of evaluating novel therapeutic approaches in patients with early-stage breast
cancer. PCR is a reasonable surrogate endpoint for patients with TNBC and HER2-positive
breast cancers, and it has been consistently shown to be associated with improved
outcomes. In patients with HR-positive breast cancer, the use of pCR as an endpoint is less
useful, and other endpoints,such as changes in Ki-67, may be more reasonable.
Denduluri N et al 2018In addition to its impact on surgery, the neoadjuvant setting offers a valuable
opportunity to monitor individual tumour response. The effectiveness of standard and/or potential new
therapies can be tested in the neoadjuvant pre-surgical setting. It can potentially help to identify markers
differentiating patients that will potentially benefit from continuing with the same or a different adjuvant
treatment enabling personalised treatment.
Predicting therapy benefit, modelling breast cancer dormancy, and the development of drug resistance.
Selli C et al, 2019; Dittmer J, 2017; Sosa MS et al, 2014Processing and Reporting of Breast Specimens in the Neoadjuvant Setting
Clinical and research tissue sampling and indicators of treatment effectiveness in
the traditional setting (A) and in the neoadjuvant setting (B).
Bossuty V, 2018Expression of cell-cycle regulation markers: KI67,MCM2, Cyclin A, PHH3
We aimed to analyze the expression of cell-cycle regulation markers
– minichromosome maintenance protein 2(MCM2), Ki-67, Cyclin-A and phosphohistone-H3 (PHH3) −
in pre-treatment CB of BC in correlation with known predictive and prognostic factors.
-52 CB obtained prior to neoadjuvant therapy were analyzed.
All investigated markers showed higher expression in high grade and in TNBC(p < 0.01 and p < 0.05,
respectively). H R negative tumors showed significantly higher expression of Ki-67 (p < 0.01),
MCM2 (p < 0.01) and Cyclin A (p < 0.01) than HRpositive ones.
Tumors with increased TIL showed significantly higher Ki-67 expression (p = 0.04).
Pattern analysis suggested that novel cell-cycle marker-based subgrouping reveals predictive and
prognostic potential. Tumors with high MCM2, Cyclin A or PHH3 expression showed significantly higher
rate of pathological complete remission.
Tumors with early relapse (progression-free survival ≤2 years) and shortened OS also show a higher
rate of proliferation. Our cell cycle marker (Ki-67, MCM2, Cyclin A, PHH3) based testing could identify
tumors with worse prognosis, but with a favorable response to primary systemic therapy.
All tested marker seem to be potentially applicable to delineate a patient group with biologically aggressive
breast tumors to be suitable to PST
The pattern of cell-cycle activity could also be useful for predicting early relapse, but our findings need to
be further substantiated in larger patient cohorts, Loddo
Tokes T.et al 2019How the cell cycle impacts on disease progression
We evaluated nuclear protein markers either expressed throughout (Ki67, MCM2),
from post G1 (Cyclin A) or in M-phase (PHH3) of the cell cycle and
their connections with the routinely used predictive and prognostic factors in breast cancer
Loddo et al. already suggested a novel approach in the assessment of CB using proliferation
activity to differentiate between patient groups with different therapeutic sensitivity and prognosis.
They assessed different, relatively phase-specific markers of the cell-cycle paralelly and form subgroups
of the patients based on the relative ratio of tumor cells overexpressing G1/S/G2 and M phase markers.
Based on their hypothesis we formed five patient groups concerning the expression of MCM2, Cyclin A
and PHH3. Our results suggested that cell cycle marker-based subgrouping performed on CB could be
used to accurately differentiate between tumors with different response to PST and prognosis.
In our study we mostly investigated tumors fit to the ‘phenotype III/actively cycling’
tumor group of the Loddo study (this group corresponds to Group III, IVan d V of our study)
-Only two patients could be classified to ‘phenotye II/G1-delayed/arrested’ tumors of the
Loddo study (this group corresponds to Group II of our study) in whom classic S and M cell-cycle-phase-
targeted agents − like the widely used taxane and anthracyclin chemotherapies − may not be as effective
than in actively cycling cells (amongst these patients pCR was not observed in our study and the response
to the applied therapy was minimal). These tumors are more likely to benefit from G1-phase targeted
agents or non-cell-cycle-specific anticancer drug
Loddo M et, 2009; Tokes t et al, 2019KI67 e TILs
Results: High Ki-67 was associated
with more pathological complete responses (pCRs) events (odds ratio: 3.10; 95% CI: 2.52–
3.81; 53 studies, 10,848 patients) regardless of HR+, HER2+ and TNBC types.
Conclusion: High Ki-67 before NAC was a predictor for pCR in neoadjuvant setting
for breast cancer patients
Acs B et al, 2017; Schlotter CM et al, 2017;Kurozumi S et al, 2019TILs
TILs PARAMETRO PREDITTIVO DI RISPOSTA A NAT
Trials overall include a total of 2,323 patients.Predictive associations of TILs
Pathology (2017)TILs e CELLULARITA’ TUMORALE
Hwang HW, et al, 2019; Nuciforo P, et al, 2017Changes in TILs from baseline to day 15 in 134 cases
Nuciforo P, et al, 2017TILs comparison CB vs SS
220 cases . In the CNBs, all cores containing invasive tumor cells were evaluated. Because true tumor
borders may be unclear in CNBs.
TIL scores were subclassified as low (≤ 10%), intermediate (11–59%), and high (≥ 60%).
The TIL scores were also divided into two groups based on the 60% cut-off value:
low/intermediate < 60%) and high (≥ 60%)
10% 30%
50% 80%
Cha YI et al, 2018, Salgado R et al, 2014; Yang X et al, 2018TILs RIPRODUCIBILITA’ e STANDARDIZZAZIONE . Multiple scientific publications have reported clinically significant results regarding evaluation of TIL in BC and therapy response, and prognosis. . Despite significant clinical results TIL evaluation may not be completely ready for introduction into routine clinical practice due to interobserver variance and the lack of standardization. . With the combined effort of a large international group of breast pathologists that we present here, we believe that this work presents a major step toward resolving these limitations. This opens the way for standardized reporting of tumor immunological parameters in diagnostic clinical practice.
NAT- IL PATOLOGOGO-CARCINOMA HER2 POSITIVO- TIL DENKERT, 2018; ASANO, 2018, IGNATIADIS 2019, YANG 2018, WON HWANG 2018
AP-FERRARA : 484 IBC CNB vs SE
- 484 IBC Pts,
- Median age 66y
- Ductal /NAS 74%
- Lobular 13%
- G2 67%
- pT1 67%
- pN0 74%
CONCORDANZA ER 96,7%, PR 90,6%, KI67 81,2% HER2 93%Concordanza diagnostica 58 centri partecipanti
30 Veneto
6 Lazio
5 Emilia
5 Piemonte
4 Toscana
2 Sardegna
1 Sicilia
1 Puglia
1 Marche
1 Liguria
1 Friuli
1 Campania2012: nasce GIPaM 2013: (Ferrara) stesura linee guida campionamento/refertazione 2014 (Firenze): primo confronto su vetrini virtuali 2015 (Milano) 2016 (Genova) 2017 (Napoli) 2018 (Roma) 2019 (Bologna)
CONCORDANZA DIAGNOSTICA FATTORI PROGNOSTICO-PREDITTIVI 2018
10 CASI DA CORE BIOPSY
1)Perché refertazione di core-biopsy?
- opzione neoadiuvante sempre più diffusa
- inquadramento preciso
Istotipo - previsione risposta
Grado/grado nucleare -confronto con campione chirurgico
TILs -core-biopsy unico materiale in PCR
Cellularità
ER 2) Utilizzo da parte degli Oncologi
PGR
KI67
HER 2
Isabella Castellano- Francesca PietribiasiCONCORDANZA DIAGNOSTICA
Isabella Castellano- Francesca Pietribiasicentrodisenologiaferrara@ospfe.it
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